Mukhopadhyay Shreya, Manolaridis Ioannis, Warren Christopher, Tang Aimin, O'Donnell Gregory, Luo Bin, Staupe Ryan P, Vora Kalpit A, Chen Zhifeng
Infectious Diseases and Vaccine Research, Merck & Co., Inc., Rahway, NJ 07065, USA.
Protein and Structural Chemistry, Merck & Co., Inc., Rahway, NJ 07065, USA.
Vaccines (Basel). 2025 Jan 2;13(1):35. doi: 10.3390/vaccines13010035.
The respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in children and adults. With nearly everyone infected by the age of five, there is an opportunity to develop booster vaccines that enhance B-cell immunity, promoting potent and broadly neutralizing antibodies. One potential approach involves using anti-idiotypic antibodies (anti-IDs) to mimic specific antigenic sites and enhance preexisting immunity in an epitope-specific manner. RB1, a monoclonal antibody (mAb) that binds to site IV of the RSV fusion (RSV F) protein, is a potent and broadly neutralizing against RSV A and B viruses. It is the precursor for MK1654 (clesrovimab), which successfully completed a Phase III clinical trial. In this study, we isolated two anti-IDs, 1A6 and 1D4, targeting RB1 CDR regions, demonstrating that 1A6 competes fully with RSV F in binding to RB1. We resolved the RB1-1A6 and RB1-1D4 Fab-Fab complex structures and proved that 1A6 mimics the RSV F site IV better than 1D4. In an immunogenicity study, mice primed with RSV F and boosted with 1A6 Fab showed a site IV-specific antibody response with a concurrent increase in RSV virus neutralization. These results suggest that anti-IDs could be potentially used as booster vaccines for specific epitopes.
呼吸道合胞病毒（RSV）是儿童和成人下呼吸道感染的主要原因。几乎每个人在五岁时都会感染，因此有机会开发增强B细胞免疫力、促进产生强效且具有广泛中和作用抗体的加强疫苗。一种潜在方法是使用抗独特型抗体（抗-IDs）来模拟特定抗原位点，并以表位特异性方式增强已有的免疫力。RB1是一种与RSV融合（RSV F）蛋白的IV位点结合的单克隆抗体（mAb），对RSV A和B病毒具有强效且广泛中和作用。它是MK1654（clesrovimab）的前体，MK1654已成功完成III期临床试验。在本研究中，我们分离出两种靶向RB1互补决定区（CDR）的抗-IDs，即1A6和1D4，证明1A6在与RB1结合时能完全与RSV F竞争。我们解析了RB1-1A6和RB1-1D4 Fab-Fab复合物结构，并证明1A6比1D4能更好地模拟RSV F的IV位点。在一项免疫原性研究中，用RSV F免疫并用1A6 Fab加强免疫的小鼠表现出IV位点特异性抗体反应，同时RSV病毒中和作用增强。这些结果表明抗-IDs可能潜在地用作特定表位的加强疫苗。
